Showing papers by "Angelo A. Manfredi published in 2009"
TL;DR: Exogenous macrophages involved in tissue remodeling appear as players in the natural history of endometriosis, required for effective vascularization and ectopic lesion growth.
Abstract: The mechanisms that sustain endometrial tissues at ectopic sites in patients with endometriosis are poorly understood. Various leukocytes, including macrophages, infiltrate endometriotic lesions. In this study, we depleted mouse macrophages by means of either clodronate liposomes or monoclonal antibodies before the injection of syngeneic endometrial tissue. In the absence of macrophages, tissue fragments adhered and implanted into the peritoneal wall, but endometriotic lesions failed to organize and develop. When we depleted macrophages after the establishment of endometriotic lesions, blood vessels failed to reach the inner layers of the lesions, which stopped growing. Macrophages from patients with endometriosis and experimental mice, but not nonendometriotic patients who underwent surgery for uterine leiomyomas or control mice, expressed markers of alternative activation. These markers included high levels of scavenger receptors, CD163 and CD206, which are involved in both the scavenging of hemoglobin with iron transfer into macrophages and the silent clearance of inflammatory molecules. Macrophages in both inflammatory liquid and ectopic lesions were equally polarized, suggesting a critical role of environmental cues in the peritoneal cavity. Adoptively transferred, alternatively activated macrophages dramatically enhanced endometriotic lesion growth in mice. Inflammatory macrophages effectively protected mice from endometriosis. Therefore, endogenous macrophages involved in tissue remodeling appear as players in the natural history of endometriosis, required for effective vascularization and ectopic lesion growth.
310 citations
TL;DR: The polarization of macrophages dramatically skews the secretion of high mobility group box 1 (HMGB1), TNF‐α, vascular endothelial growth factor, and metalloproteinase 9 (MMP‐9), molecules involved in the regulation of cell diapedesis and migration, and demonstrates their ability to attract stem cells, which is conserved throughout their polarization.
Abstract: Inflammatory macrophages recruited at the site of damaged muscles progressively acquire an alternative activation profile. Inflammatory (M1) and alternatively activated (M2) macrophages exert various and even opposite functions. M1 cells amplify tissue damage, and M2 cells dispose of necrotic fibers and deliver survival signals to myogenic precursors, finally supporting healing. A critical step in muscle healing is the recruitment of myogenic stem cells, including vessel-associated stem cells (mesoangioblasts), which have been demonstrated to home to damaged skeletal muscle selectively and preferentially. Little information is available about the signals involved and the role played by infiltrating macrophages. Here, we report that the polarization of macrophages dramatically skews the secretion of high mobility group box 1 (HMGB1), TNF-alpha, vascular endothelial growth factor, and metalloproteinase 9 (MMP-9), molecules involved in the regulation of cell diapedesis and migration. All polarized macrophage populations were strikingly effective at inducing mesoangioblast migration. By means of specific inhibitors, we verified that the recruitment of mesoangioblasts requires the secretion of HMGB1 and TNF-alpha by M1 cells and of MMP-9 by M2 cells. Together, these data demonstrate a feature, unrecognized previously, of macrophages: their ability to attract stem cells, which is conserved throughout their polarization. Moreover, they open the possibility of novel strategies, aimed at interfering selectively with signals that recruit blood-derived stem cells toward pro- or anti-inflammatory macrophages.
221 citations
TL;DR: The study described herein, identifies the first member of the TGF β/BMP family of stem cell regulators as a novel tolerogenic factor released by NPCs, and identifies this pathway as an efficient tool for vaccination therapy in autoimmune inflammatory conditions.
Abstract: Background The systemic injection of neural stem/precursor cells (NPCs) provides remarkable amelioration of the clinico-pathological features of experimental autoimmune encephalomyelitis (EAE). This is dependent on the capacity of transplanted NPCs to engage concurrent mechanisms of action within specific microenvironments in vivo. Among a wide range of therapeutic actions alternative to cell replacement, neuroprotective and immune modulatory capacities of transplanted NPCs have been described. However, lacking is a detailed understanding of the mechanisms by which NPCs exert their therapeutic plasticity. This study was designed to identify the first candidate that exemplifies and sustains the immune modulatory capacity of transplanted NPCs. Methodology/principal findings To achieve the exclusive targeting of the peripheral immune system, SJL mice with PLP-induced EAE were injected subcutaneously with NPCs and the treatment commenced prior to disease onset. NPC-injected EAE mice showed significant clinical improvement, as compared to controls. Exogenous NPCs lacking the expression of major neural antigens were reliably (and for long-term) found at the level of draining lymph nodes, while establishing sophisticated anatomical interactions with lymph node cells. Importantly, injected NPCs were never found in organs other than lymph nodes, including the brain and the spinal cord. Draining lymph nodes from transplanted mice showed focal up-regulation of major developmental stem cell regulators, such as BMP-4, Noggin and Sonic hedgehog. In lymph nodes, injected NPCs hampered the activation of myeloid dendritic cells (DCs) and steadily restrained the expansion of antigen-specific encephalitogenic T cells. Both ex vivo and in vitro experiments identified a novel highly NPC-specific-BMP-4-dependent-mechanism hindering the DC maturation. Conclusion/significance The study described herein, identifies the first member of the TGF beta/BMP family of stem cell regulators as a novel tolerogenic factor released by NPCs. Full exploitation of this pathway as an efficient tool for vaccination therapy in autoimmune inflammatory conditions is underway.
133 citations
TL;DR: The data suggest that the interaction between circulating platelets and neutrophils influences innate immune functions, possibly contributing to regulate vascular inflammation.
128 citations
TL;DR: The data indicate that HMGB1 release is required for CXCL12 ability to attract myeloid–derived cells and reveal a functional interaction between the two molecules that possibly contributes to the regulation of leukocyte recruitment and motility.
Abstract: HMGB1 finely tunes the function of DCs, thus influencing their maturation program and eventually the establishment of adaptive, T cell-dependent immune responses. Moreover, it promotes the up-regulation of receptors for lymph node chemokines, regulates the remodeling of the cytoskeleton of migrating cells, and sustains their journey to secondary lymphoid organs via a RAGE-dependent pathway. The inflammatory properties of HMGB1 depend at least partially on the ability to complex with soluble moieties, including nucleic acids, microbial products, and cytokines. Here, we show that bone marrow-derived mouse DCs release HMGB1 during CXCL12-dependent migration in vitro. Macrophages share this property, suggesting that it may be a general feature of CXCL12-responsive leukocytes. The chemotactic response to rCXCL12 of DCs and macrophages abates in the presence of the HMGB1 antagonist BoxA. HMGB1 secreted from DCs and macrophages binds to CXCL12 in the fluid phase and protects the chemokine conformation and function in a reducing environment. Altogether, our data indicate that HMGB1 release is required for CXCL12 ability to attract myeloid-derived cells and reveal a functional interaction between the two molecules that possibly contributes to the regulation of leukocyte recruitment and motility.
121 citations
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TL;DR: The immune system relies on specific signaling molecules to dampen its response to injury while maintaining the capacity to fight infection.
Abstract: The immune system relies on specific signaling molecules to dampen its response to injury while maintaining the capacity to fight infection.
116 citations
TL;DR: Endogenous signals of tissue injury provide a code for switching the outcome of the presentation of autoantigens towards results as diverse as T-cell-mcdiated protective immunity, tissue repair, persistent inflammation and autoimmunity, or tolerance.
Abstract: Two events characterize tissue injury and sterile inflammation: (1) generation/release of autoantigens, and (2) generation of homeostatic inflammatory signals. Homeostatic signals recruit leukocytes and promote cell migration and division to replace injured cells. Moreover, they activate antigen-presenting phagocytes, in particular, dendritic cells (DCs), in anticipation of microbial invasion. Activated DCs undergo a differentiation process, referred to as maturation, and migrate to secondary lymphoid organs. Maturing DCs upregulate the molecular machinery required for the priming of naive T cells, including T lymphocytes recognizing autoantigens, which represent a substantial fraction of the host T-cell repertoire. Recent data indicate that cues generated at sites of injury shape T-cell clonal expansion, regulating sensitivity to activation-dependent apoptosis and commitment towards a Th1, Th2, Th7, or regulatory T-cell fate. Endogenous signals of tissue injury, also called damage-associated molecular patterns (DAMPS) or alarmins, therefore provide a code for switching the outcome of the presentation of autoantigens towards results as diverse as T-cell-mcdiated protective immunity, tissue repair, persistent inflammation and autoimmunity, or tolerance.
66 citations
TL;DR: Recent studies have revealed homeostatic roles of vascular inflammation and identified the action of humoral innate immunity on the activation of circulating leucocytes, platelets and endothelial cells.
Abstract: Vessel walls are the primary inflammatory sites in systemic vasculitides. In most cases the initiating event is unknown, and a self-sustaining circuit attracts and activates inflammatory leucocytes in the wall of vessels of various size and anatomical characteristics. Recent studies have revealed homeostatic roles of vascular inflammation and have identified the action of humoral innate immunity, in particular injury-associated signals and acute phase proteins, on the activation of circulating leucocytes, platelets and endothelial cells. These advances have provided clues to the molecular mechanisms underlying the vicious circle that maintains and amplifies vessel and tissue injury.
50 citations
TL;DR: The data document for the first time the presence of a local Ag-driven clonal evolution of B cells in human atherosclerotic plaques.
Abstract: Recent data indicated that adaptive immunity is involved in the process of atherogenesis. Oligoclonal recruitment of T lymphocytes has been described in coronary plaques of patients with acute coronary syndrome. However, the nature of immune response remains to be determined. In the present study, we examined the Ab response in six coronary plaques obtained by endoluminal directional atherectomy. The IgG1/κ-coding gene repertoires of B lymphocytes present in circulating blood and in coronary plaques were cloned and analyzed. In all of the six plaques, we observed 1) a skewed usage of heavy and light IgG1/κ Ab-coding genes, 2) an oligoclonal distribution of V K , J K , and V H , D H , and J H genes with overrepresentation of some rarely used IgG genes, and 3) the unequivocal signs of Ag-driven clonal expansion and evolution of B cells. The data document for the first time the presence of a local Ag-driven clonal evolution of B cells in human atherosclerotic plaques.
33 citations
TL;DR: Activated circulating leukocytes and platelets could contribute to indolent vessel inflammation and possibly to thromboembolic events in patients with systemic large vessel vasculitis.
Abstract: Ischemia is a leading causes of morbidity in giant cell arteritis (GCA). We studied circulating platelets and leukocytes in patients with GCA and with polymyalgia rheumatica. Normal healthy donors (>60 a) served as controls. Patients had a significantly greater fraction of platelets expressing P-selectin, of platelet-Nph and platelet-Mo aggregates, and of Nph and Mo expressing tissue factor. These differences were correlated with the percentage of platelets expressing P-selectin and were not influenced by clinical features or by systemic inflammation. Activated circulating leukocytes and platelets could contribute to indolent vessel inflammation and possibly to thromboembolic events in patients with systemic large vessel vasculitis.
28 citations
TL;DR: Giant cell arteritis rapidly responds to high-dose corticosteroids, however, smouldering arterial inflammation can persist despite the absence of symptoms and altered acute phase reactants, and Chromogranin A in particular is a candidate marker linking neurogenic inflammation and vascular inflammation.
Abstract: Giant cell arteritis (GCA) rapidly responds to high-dose corticosteroids. However, smouldering arterial inflammation can persist despite the absence of symptoms and altered acute phase reactants. In patients that are refractory, symptoms relapse during steroid tapering and vascular complications may develop. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level are not sensitive enough markers to detect refractory disease.1 The neuroendocrine system regulates innate and acquired immune responses, influencing cytokine synthesis and limiting tissue damage via release of neurotransmitters and peptides in peripheral tissues. Chromogranin A in particular is a candidate marker linking neurogenic inflammation and vascular inflammation.2 We investigated by ELISA, as described previously,3 the …
TL;DR: Patients with acute coronary syndromes and low circulating C-reactive protein levels are more sensitive to the anti-inflammatory action of apoptotic cells: this suggests the existence of an enhanced anti- inflammatory feedback circuit, which could contribute to protect from plaque instability.